Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B.

Interacts through its PDZ domains with ANO2 and NETO1. Interacts with KCNJ4 (PubMed:11997254). Interacts through its first two PDZ domains with GRIN2A, GRIN2B, GRIN2C, GRIN2D, ASIC3, certain splice forms of GRIN1, KCND2, CXADR, SYNGAP1, KCNA1, KCNA2, KCNA3, KCNA4, ERBB4, LRRC4; LRRC4B and SEMA4C. Interacts through its first PDZ domain with GRIK2, KCNA4 and CRIPT. Interacts through its second PDZ domain with the PDZ domain of NOS1 or the C-terminus of CAPON. Interacts through its third PDZ domain with NLGN1 and CRIPT, and probably with NLGN2 and NLGN3. Interacts through its guanylate kinase-like domain with DLGAP1/GKAP, DLGAP2, DLGAP3, DLGAP4, MAP1A, BEGAIN, SIPA1L1 and KIF13B (PubMed:9115257, PubMed:9756850). Isoform 2 interacts through an L27 domain with HGS/HRS and the first L27 domain of CASK. Interacts with ADR1B, ANKS1B and PRR7 (PubMed:15629447). May interact with HTR2A. Interacts with ADAM22, KLHL17 and LGI1. Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1, LRFN2 and LRFN4, but not with LRFN3 nor LRFN5. Interacts (via N-terminal tandem pair of PDZ domains) with GPER1 (via C-terminus tail motif); the interaction is direct and induces the increase of GPER1 protein levels residing at the plasma membrane surface in a estradiol-independent manner (PubMed:23300088). Interacts (via N-terminus tandem pair of PDZ domains) with NOS1 (via N-terminal domain) (PubMed:23300088). Interacts with SHANK3.

High levels in postsynaptic density of neurons in the forebrain. Also in presynaptic region of inhibitory synapses formed by cerebellar basket cells on axon hillocks of Purkinje cells.

Cellular localization of substrate by fusion with fluorescent protein, Inhibition of palmitoylation with 2-bromopalmitate, Over-expression of palmitoyltransferase, Labeling of substrate with [3H]palmitate

ABE (Acyl-Biotin Exchange), Cleavage of thioester bonds with NH2OH, Co-immunoprecipitation of palmitoyltransferase and substrate, Labeling of substrate with 17-ODYA (17-octadecynoic acid), Point mutation of substrate, inhibition of thioesterase with palmostatin B, over expression of substrate